This application for renewal of our longstanding Program Project is based on a highly focused, integrated and interactive effort to examine the hypothesis that mitochondrial antioxidants are capable of resisting age-related disease and improving health and function in multiple organ systems in mammals. This builds on past progress, including observations that mice overexpressing mitochondrially targeted catalase have extended lifespan, improved cardiac, and muscle health and resistance to epithelial cancers. We therefore have developed an increasing focus on health and healthspan, including study of acute models of decline in organ function that can serve as surrogate assays for similar disorders in aging. In this Program Project we propose four Projects to apply this approach to disorders of aging in which mitochondrial reactive oxygen species (ROS) and ROS-induced damage play an important role: 1) Mitochondrial ROS and cardiac aging; 2) Mitochondrial ROS and neurodegenerative disease; 3) Mitochondrial ROS and protection from epithelial cancers in aging; 4) Mitochondrial-targeted antioxidants, aging and AZT in skeletal muscle dysfunction. The Projects are supported by four Cores: 1) Administrative; 2) Mouse pathobiology; 3) Proteomics; 4) Mitochondrial protective chemistry. In each of these Projects and Cores we seek to understand the mechanisms underlying the role of mitochondrial ROS in aging and healthspan, as well as pursuing the translational goal of identifying mitochondrial protective drugs to deliver these healthspan benefits to humans.